Project Summary/Abstract There is a fundamental gap in understanding the molecular mechanisms underlying central nervous system (CNS) insulin transport. This represents an important gap due to the importance of CNS insulin in memory. The long-term goal is to understand the impact of obesity on both normal and pathological brain aging. The objective of this particular application is to investigate the effect of high-fat diet (HFD) induced obesity on CNS insulin and cognitive function. Obesity-induced effects on CNS insulin transport may render the brain susceptible to memory impairment. The central hypothesis is that HFD reduces hippocampal insulin transport, thereby impairing cognitive function. This hypothesis is based on preliminary data produced in the applicant's laboratory. The rationale for the proposed research is that understanding the impact of CNS insulin on brain function will set the stage for the development of innovative approaches to mitigate obesity-associated cognitive decline. Thus, this hypothesis will be tested by pursing two specific aims: 1) test hypothesis that HFD reduces hippocampal insulin transport and 2) test hypothesis that impairing CNS insulin transport results in cognitive deficits. Under Aim 1, molecular techniques in HFD mice will be utilized to evaluate the uptake of insulin into the hippocampus. In addition, the changes in insulin receptor expression and signaling proteins will be evaluated in isolated hippocampal microvessels, which represent the blood brain barrier. Under the second aim, a transgenic mouse lacking the insulin receptor specifically in vascular endothelial cells will be used to evaluate the role of the insulin receptor in CNS insulin transport and the impact on cognitive function. The approach is innovative, because it utilizes an animal model specifically designed to understand the mechanisms underlying obesity-related impairments in CNS insulin transport and its impact on cognitive function. The proposed research is significant, because it is expected it is expected to lead to the development of targeted therapies to delay or prevent cognitive decline. Ultimately, the results of this work may also be useful in improving cognitive function associated with neurological disorders such as Mild Cognitive Impairment or Alzheimer's disease.